17-oxygenated 9alpha-fluoroandrost-4-en-3-ones



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3,029,258 17-0XYGENATED 9u-FLUOROANDROST- 4-EN-3-ONES Clarence G. Bergstrom, Chicago, Ill., and Raymond M. Dodson, Minneapolis, Minn., assignors to G. D. Searle & Co., Chicago, Ill., a corporation of Delaware No Drawings. Filed May 5, 1961, Ser. No. 107,941 Claims. (Cl. 260-3973) The present invention is concerned with novel 9a-fluorosteroids and, more particularly, with 17-oxygenated 9ozfluoroandrost-4-en-3-ones as represented by the following structural formulae wherein X is hydrogen or a lower alkanoyl radical, and R is hydrogen or a hydrocarbon radical selected from the class consisting of lower alkyl, lower alkynyl, and lower alkenyl radicals.

Hydrocarbon radicals represented by R are exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, vinyl, propenyl, butenyl, pentenyl, hexenyl, and the branched-chain isomers thereof.

The lower alkanoyl radicals encompassed by the X term are typified by formyl, acetyl, propionyl, butyryl, valeryl, caproyl, and the branched-chain isomers thereof, said groups being the acyl radicals of alkanoic acids con taining fewer than 7 carbon atoms.-

Starting materials suitable for the manufacture of the instant compounds are exemplified by 11,8-hydroxy-androst-4-ene-3 l 7-dione, 9a-hydroxyandrost-4-ene-3 17-dione, androsta-4,9(1l)diene-3,17-dione, and the corre sponding l7 3-hydroxy and l7B-(lower alkanoyl)oxy compounds. As a specific example, llfl-hydroxyandrost- 4-ene-3,17-dione is treated with a solution of hydrogen fluoride in pyridine to afford 9a-fiuoroandrost-4-ene-3,17- dione.

kynyl-l7fi-hydroxy compounds of this invention involves the conversion of the aforementioned 9 u-fiuoro-androst- 4-ene-3,17-dione'to the corresponding 3-enol ether, which is allowed to react with the appropriate alkyne in the presence of an alkaline catalyst. Thus, the aforementioned 9a-fluoroandrost-4-ene-3,l7-dione is treated with ethanol and ethyl orthoformate in the presence of p-toluenesulfonic acid to yield 3-ethoxy-9a-fluoroandrosta-3,5dien- 1'7-one, which is allowed to react with acetylene in the presence of potassium hydroxide to afiord, after hydrolysis of the enol ether, 17a-ethylnyl-9a-fluoro17(3-hydroxyandrost-4-en-3-one.

Partial hydrogenation of the aforementioned l7a-alkynyl-l7B-hydroxy compounds affords the corresponding 17a-a1kenyl-17B-hydroxy compounds, which can be further hydrogenated to produce the 17a-alkyl-17flhydroxy compounds of this invention. These processes are specifically illustrated by the reaction of 17a-ethy1nyl-9ufluoro-l7B-hydroxyandrost-4-en-3-one with one molecular equivalent of hydrogen in the presence of 5% palladiumon-calcium carbonate catalyst to yield 9a-fluoro-l7e-hydroxy-17a-vinylandrost-4-en-3-one, which is allowed to react with hydrogen in the presence of 5% palladium-oncarbon catalyst to afford l7oc-ethyl-9a-fluoro-17B-hydroxyandrost-4-en-3-one.

Acylation of the instant Una-(hydrocarbon substituted)- 17B-hydroxy compounds affords the corresponding 1713- alkanoates of this invention. Typically, 17a-ethynyl-9afluoro-l7,6-hydroxyandrost-4-en-3-one is treated vw'th acetic anhydride in pyridine to produce 17,6-acetoxy-17aethylnyl-9a-fluoroandrost-4-en-3-one.

The compounds of the present invention display valuable pharmacological properties. They are, for example, hormonal agents as evidenced by their anabolic and androgenic properties. In addition, the compounds containing a 17-hydrocarbon substituent are progestational agents.

This application is a continuation-in-part of our copending application, Serial No. 773,560, filed November 13, 1958.

The present invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only and are not to be construed as limiting the invention either in spirit or in scope. It will be apparent to those skilled in the art of organic synthesis that many modifications of materials and methods may be practiced without departing from this invention. In these examples, temperatures are given in degrees Centigrade C.) and quantities of materials in parts by weight, except where otherwise noted. Optical rotations are carried out in chloroform solution except where otherwise indicated.

Example I A concentrated solution of hydrogen fluoride in pyridine is prepared by passing a stream of anhydrous hydrogen fluoride through parts of pyridine contained in a large vessel. During the addition the temperature is maintained below 50 by means of a cooling bath. The resulting solution contains about 74.8% of hydrogen fluoride and about 25.2% of pyridine.

A solution of 0.5 part of 1lfi-hydroxyandrostl-ene- 3,17-dione in 10 parts of the aforementioned hydrogen fluoride-pyridine reagent is stored at room temperature for about 29 hours, then treated with 90 parts of ethyl acetate and 50 parts of water. The organic layer is separated, washed successively with water, saturated aqueous sodium bicarbonate, and water, dried over anhydrous sodium sulfate, then concentrated to afford a yellow crystalline product. These yellow crystals are dissolved in benzene and the resulting solution is chromatographed on a silica gel column. The column is then developed with benzene and benzene solutions containing increasing amounts of ethyl acetate. The 10% ethyl. acetate in benzene eluate yields a fraction which is recrystallized from acetone-petroleum ether to afford 9a-fiuoroandrost-4-ene- 3,17-dione, M.P. about 227-228". This compound possesses infrared absorption maxima at about 5.75, 6.00, 7.46, 8.05, 9.60, 9.75, 11.28, and 11.56 microns, and also an ultraviolet absorption maximum at about 237 millimicrons with a molecular extinction coefiicient of about 17,800.

Example 2 A solution of 2 parts of 11,8,17B-dihydroxyandrost-4- en-3-one in 20 parts of hydrogen fluoride-pyridine reagent is stored at room temperature for about 4 hours, then treated with 50 parts of Water and parts of ethyl acetate. The ethyl acetate solution is washed successivewith 15% ethyl acetate in benzene and recrystallization of the resulting fraction from acetone-petroleum ether afiords 9a-flu0ro-17fi-hydroxyandrost-4-en-3-one, M.P. about 206-207.

Example 3 A solution of 1.1 parts of 17B-acetoxy-11p-hydroxyandrost-4-en-3-one in 11 parts of hydrogen fluoridepyridine reagent is kept at for about 4 hours, then is treated with 225 parts of ethyl acetate and 100 parts of water. The organic layer is separated, washed successively with water, aqueous sodium bicarbonate, and water, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo. The pale yellow syrupy material obtained is crystallized from acetone-petroleum ether to produce 17,8-acetoXy-9a-fluoroandrost-4-en-3-one, M.P. about 197.5-198.5. This substance is further characterized by an ultraviolet maximum at about 237.5 millimicrons with a molecular extinction coefficient of about 16,800, and also a specific rotation of about +7 1?.

. Example 4 A mixture of 0.2 part of 9a-fluoro-17fi-hydroxyandrost- 4-en-3-one, 2 parts of pyridine and 2 parts of 'pr'opionic anhydride is allowed to stand at room temperature for about 15 hours, then is diluted with cold water. The resulting crystalline precipitate is collected by filtration, then recrystallized from acetone-petroleum ether to produce 9a-fiuoro-17 9-propionoxyandrost-4-en-3-one, M.P. about 163-165; [a] =+62.0. It is characterized further by an ultraviolet absorption maximum of about 238 millimicrons with a molecular extinction coefficient of about 17,300.

Example 5 A solution of 5.85 parts of 9a-fiuoroandrost-4-ene-3,17- dione, 0.58 part of p-toluenesulfonic acid monohydrate, 4.6 parts of anhydrous ethanol, and 53.5 parts of ethyl orthoforrnate in 288 parts of purified dioxane is stored at room temperature, under nitrogen, for about 7 hours. The yellow reaction mixture is then poured into 2,500 parts of saturated aqueous sodium bicarbonate, and this aqueous mixture is extracted with benzene. The benzene layer is washed with water and dried over anhydrous sodium sulfate, then evaporated to dryness at reduced pressure. The resulting residue is dissolved in benzene, and this organic solution is chromatographed on alumina. Elution of the column with benzene affords a crystalline fraction, which is recrystallized from benzene-pentane to produce pure 3-ethoxy-9a-fluoroandrosta-3,S-dien-17-one, M.P. about 153-161". This substance displays infrared maxima at about 5.76, 6.03, 6.13, 8.51, and 11.69 microns and also an ultraviolet absorption maximum at about 240 millimicrons with a molecular extinction coefficient of about 21,400.

Example 6 A solution containing 20 parts by volume of diethylene glycol monomethyl ether and 280 parts by volume of diethylene glycol dimethyl ether is heated in a 139 bath, under nitrogen, then treated with 53.4 parts of potassium hydroxide with vigorous stirring. Stirring is continued for about 30 minutes, during which time the bath temperature rises to 146. The alkaline mixture is then allowed to cool with stirring, resulting in a silky disperson.

A stream of acetylene is passed over the surface of 190 parts by volume of the latter dispersion, under nitrogen, for about 2 hours, and a solution of 1.86 parts of 3- ethoxy-9a-fluoroandrosta-3,S-dien-17-one in 48 parts of diethylene glycol dimethyl ether is then added. Stirring and acetylene addition are continued for about 3 hours,

after which time the reaction mixture is poured into ice and water. The resulting aqueous mixture is extracted with ethyl acetate, and the organic extract is washed with Water, dried over anhydrous sodium sulfate, and concentrated to dryness at reduced pressure. The residue is dissolved in acetone and treated with dilute hydrochloric acid to effect hydrolysis of the enol ether. The mixture is cooled in an ice bath, then filtered to afiord 17a-ethynyl- 9a-fluoro-17,8-hydroxyandrost-4-en-3-one, M.P. about 296.5 (dec.). The product can be purified further by recrystallization from acetone to afford a sample which displays infrared maxima at about 2.92, 3.06, 4.74, 6.02, and 6.17 microns and an ultraviolet absorption maximum at about 237.5 millimicrons with an extinction coeificient of about 16,000.

Example 7 The substitution of an equivalent quantity of propyne for acetylene in the process of Example 6 results in 9afluoro-17fi-hydroxy-17a-propynylandrost-4-en-3-one.

Example 8 To a solution of 1.53 parts of 17a-ethynyl-9a-fluorol7fi-hydroXyandrost-4-en-3-one in 200 parts of pyridine is added one part of 5% palladium-on-calcium carbonate catalyst, and this mixture is stirred in a hydrogen atmosphere until one molecular equivalent of hydrogen is absorbed. The catalyst is removed by filtration and the filtrate is concentrated at reduced pressure. A solution of the residue in benzene is chromatographed on silica gel and the column is developed with benzene solutions containing increasing proportions of ethyl acetate. The 10% ethyl acetate in benzene eluate affords a fraction which is recrystallized from acetone-hexane to produce pure 9a -fluoro-17 3-hydroxy-l7a-vinylandrost-4-en-3-one, M.P. about 193.5196.5; [a] =+56.5 (1% in dioxane). This substance displays infrared absorption maxima at about 2.86, 5.98, and 6.16 microns, and a maximum in the ultraviolet at about 237.5 millimicrons with a molecular extinction coefficient of about 16,100.

Example 9 The substitution of an equivalent quantity of 9a-fluoro- 17fi-hydroxy 17a propynylandrost-4-en-3-one for 170:- ethynyl-9a-fluoro 17B hydroxyandrost-4-en-3-one in the process of Example 8 results in 9a-fiuoro-17fl-hydroxyl7a-propenylandrost-4-en-3-0ne.

Example 10 A mixture of 9.3 parts of 9a-f1uoro-l7p-hydroxy-17avinylandrost-4-en-3-one, 1,000 parts of dioxane, and 3 parts of 5% palladium-on-carbon catalyst is stirred in a hydrogen atmosphere until one molecular equivalent of hydrogen is absorbed. Removal of the catalyst by filtration affords a filtrate which is concentrated to dryness at reduced pressure. A solution of the syrupy residue in benzene is chromatographed on silica gel and the column is developed with benzene solutions containing increasing proportions of ethyl acetate. Elution with 10% ethyl acetate in benzene affords a fraction which is recrystallized from acetone-hexane to produce pure l7a-ethyl-9afiuoro-l7p-hydroxyandrost-4-en-3-one, M.P. about 198- 199"; [a] =|51 (0.5% in chloroform). An ultraviolet absorption maximum is observed at about 237.5 millimicrons with a molecular extinction coefficient of about 17,400, and infrared maxima are observed at about 2.68, 2.74, 5.98, and 6.17 microns.

Example 11 The substitution of an equivalent quantity of 9u-fluorol7/3-hydroxy 17a propenylandrost 4-en-3-one for fiuoro-17B-hydroxy 17a vinylandrost-4-en-3-one in the procedure of Example 10 produces 9a-fluoro-17B-hydroxy-l 7a-propylandrost-4-en-3-one.

Example 12 A mixture of one part of l7a-ethynyl-9a-fluoro-17,8- hydroxyandrost-4-en-3-one, 2 parts of acetic anhydride, and 5 parts of pyridine is heated at the reflux temperature for about 3 hours, then is cooled and diluted with ice and water. Extraction of this aqueous mixture with ether afiords an organic solution, which is washed successively with dilute hydrochloric acid, water, and aqueous sodium bicarbonate, then dried over anhydrous sodium sulfate, and evaporated to dryness to produce 17/3-acetoxy-17aethynyl-9a-fluoroandrost-4-en-3-one.

Example 13 The substitution of an equivalent quantity of propionic anhydride for acetic anhydride in the procedure of Example 12 results in 17a-ethynyl-9a-fluoro-17B-propionoxyandrost-4-en-3-one.

Example 14 By substituting an equivalent quantity of 9a-fiuoro-17/3- hydroxy-l7a-vinylandrost-4-en-3-one for l7a-ethynyl-9afluoro-17,8-hydroxyandrost-4-en-3-one in the procedure of Example 12 and increasing the period of reflux to about 4 hours, 17B-acetoxy-9a-fluoro-17a-vinylandrost-4-en-3- one is obtained.

Example 15 The reaction of 9u-fluoro-17 3-hydroxy-17u-vinylandrost-4-en-3-one and propionic anhydride by the process of Example 12 results in 9a-fiuoro-175-propionoxy-17uvinylandrost-4-en-3-one.

Example 16 By substituting an equivalent quantity of 17a-ethyl-9ufluoro-l7B-hydroxyandrost-4-en-3-one for 17a-ethynyl-9ozfluoro-17 8-hydroxyandrost-4-en-3-one in the process of Example 12 and increasing the period of reflux to about 6 hours, 17,8-acetoxy-17a-ethyl-9a-fluoroandrost-4-en-3- one is obtained.

Example 17 The reaction of l7ot-ethyl9u-fluoro-17 3-hydroxyandrost-4-en-3-one and propionic anhydride by the procedure of Example 12 results in 17a-ethy1-9a-fluoro-17fl propionoxyandrost-4-en-3-one.

6 What is claimed is: 1. A compound of the structural formula wherein X is selected from the group consisting of hydrogen and lower alkanoyl radicals, and R is selected from the group consisting of hydrogen, lower alkyl, lower alkynyl, and lower alkenyl radicals.

2. A compound of the structural formula H3O OH '(lower alkyl) 3O p l 3. A compound of the structural formula HBO on ""(lower alkynyl) H8O p No references cited. 

1. A COMPOUND OF THE STRUCTURAL FORMULA 